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We study a coordination game among agents in a network. The agents choose whether to take action (e.g. adopting a new technology) in an uncertain environment that yields increasing value in the actions of neighbours. We develop an algorithm that fully partitions the network into communities (coordination sets) within which agents have the same propensity to adopt. Our main finding is that a novel measure of network connectedness, which we term "social connectedness," determines the propensity to adopt for each agent. Social connectedness captures both the number of links each agent has within her community (interconnectedness) as well as the number of links she has with members of other communities who have a higher propensity to adopt (embeddedness). There is a single coordination set if and only if the network is balanced—that is, the average degree of each subnetwork is no larger than the average degree of the network. Finally, we demonstrate that contagion is localized within coordination sets, such that a shock to an agent uniformly affects this agent and all members of her coordination set but has no impact on the other agents in the network. [ABSTRACT FROM AUTHOR]

Microbial water quality is routinely examined using the fecal indicator bacteria Escherichia coli, coliform bacteria and enterococci. Several practical cases in German drinking water distribution systems indicated invertebrates such as insects or gastropods as a source for the microbiological deterioration. Therefore, we examined three genera of Gastropoda (Arion, Helix and Cepaea) for the presence of fecal indictor bacteria in excreta using standard methods. Enterococci and coliform bacteria were detected in high concentrations (mean values of 1.5 × 10 6 and 6.3 × 10 6 per gram feces, respectively). E. coli was also detected, still specification revealed that what was assigned by standard ISO-methods to be E. coli was indeed a novel species of Buttiauxella, exhibiting β-D-glucuronidase activity, thus, explaining the false-positive results. Microbiome analyses confirmed the cultural results. Enterobacteriaceae were dominant in the samples, yet only very few sequences could be assigned to Escherichia. Our study suggests, that enterococci and coliform bacteria are an integral component in the gastropod microbiome, whereas E. coli might be derived from other sources with gastropods being a vector. The results further indicate, that the current concept of fecal indicator bacteria needs to be extended, as not only humans and homeothermic animals could be a source for fecal indictor bacteria, but also gastropods need to be taken into consideration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Surface waters are one of the main sources for drinking water production, and thus microbial contamination should be as minimal as possible. However, high concentrations of coliform bacteria were detected in reservoirs and lakes used for drinking water production during summer months due to autochthonous proliferation processes. Here, we present the genomic analyses of 17 strains of Enterobacter asburiae and Lelliottia spp. proliferating in reservoirs and lakes with special focus on the hygienic relevance, antibiotic resistance, and adaptations to the oligotrophic environments. The genomes contain neither genes for the type III secretion system nor cytotoxins or hemolysins, which are considered typical virulence factors. Examination of antibiotic resistance genes revealed mainly efflux pumps and β-lactamase class C ( ampC ) genes. Phenotypically, single isolates of Enterobacter asburiae showed resistance to fosfomycin and ceftazidime. The genome analyses further suggest adaptations to oligotrophic and changing environmental conditions in reservoirs and lakes, e.g., genes to cope with low nitrate and phosphate levels and the ability to utilize substances released by algae, like amino acids, chitin, alginate, rhamnose, and fucose. This leads to the hypothesis that the proliferation of the coliform bacteria could occur at the end of summer due to algae die-off. IMPORTANCE Certain strains of coliform bacteria have been shown to proliferate in the oligotrophic water of drinking water reservoirs and lakes, reaching values above 10 4 per 100 mL. Such high concentrations challenge drinking water treatment, and occasionally the respective coliform bacteria have been detected in the treated drinking water. Thus, the question of their hygienic relevance is of high importance for water suppliers and authorities. Our genomic analyses suggest that the strains are not hygienically relevant, as typical virulence factors are absent and antibiotic resistance genes in the genomes most likely are of natural origin. Furthermore, their presence in the water is not related to fecal contamination. The proliferation in reservoirs and lakes during stable summer stratification is an autochthonic process of certain E. asburiae and Lelliottia strains that are well adapted to the surrounding oligotrophic environment.

We report the draft genome sequences of Buttiauxella spp. strains that were isolated from water and gastropods. Three isolates show fluorescence in the Colilert system, indicating unusual β-d-glucuronidase activity, and phylogenetic analyses suggest that they represent a novel species. Another strain, without β-d-glucuronidase activity, was assigned to the species Buttiauxella ferragutiae.

Study Objective: Lefamulin is a novel pleuromutilin recently approved by the FDA for the treatment of community-acquired bacterial pneumonia. Given that, lefamulin is primarily metabolized by CYP450 Phase-1 reactions, this study evaluated the pharmacokinetics of IV lefamulin in subjects with various degrees of hepatic impairment as compared with matched healthy subjects., Design: Open-label, Phase-1 clinical pharmacokinetic study., Setting: Research Study Center., Patients: Twenty-seven subjects; comprised of 11 individuals with normal hepatic function and eight each with moderate or severe hepatic impairment were included, as classified by Child-Pugh scores., Measurements and Main Results: Subjects were administered a single dose of IV lefamulin 150 mg over 1 h. Plasma was collected for 48 h and analyzed for lefamulin and its major metabolite, BC-8041, concentrations in addition to assessing lefamulin plasma protein binding. Pharmacokinetics were evaluated by noncompartmental analysis. Pharmacokinetic parameters were compared using least square geometric mean ratios. Lefamulin was well tolerated in all hepatic function groups. Statistical analyses revealed reductions in C max and increases in renal clearance for Moderate and Severe groups, as well as, the increased volume of distribution for the Severe group. Lefamulin plasma AUC mean (SD) was similar across groups at 7615 (1554), 8233 (2286), and 8938 (1640) h.ng/mL for Normal, Moderate, and Severe groups, respectively, despite decreased clearance observed primarily during terminal elimination phases. Decreased plasma-protein binding was seen in hepatically-impaired versus normal subjects., Conclusion: Lefamulin was generally well tolerated. Differences in lefamulin and BC-8041 pharmacokinetics were small, relative to the overall variability, and any changes appear to be compensated by increases in renal clearance and decreased protein binding., (© 2021 Pharmacotherapy Publications, Inc.)

Study Objective: Lefamulin is a novel IV and oral pleuromutilin recently approved for the treatment of community-acquired bacterial pneumonia (CABP). Given that renal comorbidities are common in patients admitted for CABP, understanding the pharmacokinetics of lefamulin in the face of severe renal impairment, including those requiring hemodialysis, is needed., Design: Open-label, Phase-1 pharmacokinetic study., Setting: Research Study Center., Patients: Twenty-three matched subjects were included, seven with "Normal" renal function (creatinine clearance >90 ml/min), eight with "Severe" renal impairment (glomerular filtration rate <30 ml/min/1.73 m 2 ), and eight subjects requiring hemodialysis., Measurements and Main Results: Subjects were administered a single dose of lefamulin IV 150 mg as a 1-h infusion. Subjects in the hemodialysis group started hemodialysis within 1 h after lefamulin infusion (On dialysis), as well as, on a non-dialysis day (Off dialysis). Plasma, urine, and dialysate fluid were collected for 36 h and analyzed for lefamulin and its major metabolite, BC-8041. Lefamulin was primarily excreted non-renally across groups. Statistical analyses revealed lefamulin and BC-8041 pharmacokinetics were similar between Normal and Severe groups, except for renal clearance, which decreased in Severe subjects (mean 1.3 L/h Normal vs. 0.4 L/h Severe). Likewise, lefamulin pharmacokinetics during on and off dialysis were unchanged, with lefamulin not measurably filtered in dialysate fluid. Two, three, and three subjects reported drug-related treatment-emergent adverse events (TEAE) in Normal, Severe, and Hemodialysis groups, respectively. All TEAEs were mild, except one (infusion-site reaction) that was classified as moderate., Conclusion: No dosage adjustment is required for patients with renal impairment, and lefamulin can be administered without regard to hemodialysis timing., (© 2021 Pharmacotherapy Publications, Inc.)

Background: Bosutinib is an orally bioavailable, dual Src and Abl tyrosine kinase inhibitor approved in the USA for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia following development of resistance or intolerance to prior therapy. In vitro studies demonstrated that bosutinib displays pH-dependent aqueous solubility, suggesting that concomitant administration of agents that alter gastric pH could affect bosutinib absorption., Objectives: The objectives of this study were to evaluate the effect of lansoprazole, a gastric proton pump inhibitor, on the pharmacokinetics and safety of bosutinib., Methods: This open-label, non-randomized, phase I study involved inpatients and outpatients at a single site. The study participants were healthy men or women of non-childbearing potential aged 18-50 years. Each subject received bosutinib 400 mg on Day 1, lansoprazole 60 mg on Day 14, and bosutinib 400 mg co-administered with lansoprazole 60 mg on Day 15 under fasting conditions. The main outcome measure was the effect of multiple doses of lansoprazole on the pharmacokinetic profile of a single oral dose of bosutinib., Results: A total of 24 healthy male subjects were enrolled. Co-administration with lansoprazole decreased the mean maximum plasma concentration (C(max)) of bosutinib from 70.2 to 42.9 ng/mL, and the total area under the plasma concentration-time curve (AUC) from 1,940 to 1,470 ng·h/mL. Log-transformed bosutinib pharmacokinetic parameters indicated significant between-treatment differences; the least squares geometric mean ratio for C(max) was 54 % (95 % CI 42-70) and for AUC was 74 % (95 % CI 60-90). Mean apparent total body clearance from plasma after oral administration increased from 237 to 330 L/h, and the median time to reach Cmax increased from 5 to 6 h, although this change may be related to decreased bosutinib absorption when combined with lansoprazole. When co-administered with lansoprazole, bosutinib maintained an acceptable safety profile, which was primarily characterized by diarrhea (33 %), headache (21 %), and nausea (13 %). One subject experienced serious adverse events of diverticulitis, gastritis, and duodenitis after co-administration; however, no participant withdrew because of toxicity., Conclusions: This study demonstrated that bosutinib absorption may be reduced when co-administered with lansoprazole or other proton pump inhibitors. Caution should be used with such drug combinations, as subtherapeutic exposure of bosutinib may limit its clinical antitumor activity; short-acting antacids are recommended instead.

Purpose: Bosutinib, a dual Src/Abl kinase inhibitor in development for treatment of chronic myeloid leukemia, is primarily metabolized by the CYP3A4 hepatic enzyme. This study evaluated the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects., Methods: Hepatically impaired patients were aged 18-65 years and of Child-Pugh classes A, B, or C; healthy subjects were matched by age, sex, body mass index, and smoking habits. A single oral dose of bosutinib 200 mg was administered on day 1 within 5 min after completion of breakfast., Results: Compared with healthy subjects (n = 9), maximal plasma concentration (C(max)) and area under the curve increased 2.42-fold and 2.25-fold in Child-Pugh A (n = 6), 1.99-fold and 2.0-fold in Child-Pugh B (n = 6), and 1.52-fold and 1.91-fold in Child-Pugh C patients (n = 6). Time to C(max) decreased from 4 h in healthy subjects to 2.5, 2.0, and 1.5 h in Child-Pugh A, B, and C patients, respectively; the elimination half-life increased from 55 h in healthy subjects to 86, 113, and 111 h in Child-Pugh A, B, and C patients. Bosutinib oral clearance was lower in hepatically impaired patients compared with healthy subjects. Frequently reported adverse events included prolonged QTc interval (37.0%, n = 10), nausea (11.1%, n = 3), and vomiting (7.4%, n = 2)., Conclusions: A single oral dose of bosutinib 200 mg showed acceptable tolerability in healthy subjects and in patients with mild, moderate, or severe chronic hepatic impairment.